title: Randomized controlled trial of danoprevir plus peginterferon alfa-2a and ribavirin in treatment-naïve patients with hepatitis C virus genotype 1 infection.
abstract: OBJECTIVE
  The combination of a hepatitis C virus (HCV) protease inhibitor, peginterferon, and ribavirin is the standard of care for patients with HCV genotype 1 infection. We report the efficacy and safety of response-guided therapy with danoprevir (a potent second-generation protease inhibitor), peginterferon alfa-2a (40 KD), and ribavirin in these patients.
  
  
  METHODS
  Treatment-naïve patients (N = 237) were randomly assigned to groups given 12 weeks of danoprevir (300 mg every 8 hours; 600 mg every 12 hours, and 900 mg every 12 hours) or placebo plus peginterferon alfa-2a and ribavirin, followed by peginterferon alfa-2a and ribavirin. Patients given danoprevir who had an extended rapid virologic response (eRVR4-20: HCV RNA <15 IU/mL during weeks 4-20) stopped therapy at week 24; those without an eRVR4-20 continued therapy to 48 weeks. Patients who were given placebo received 48 weeks of peginterferon alfa-2a and ribavirin. The primary efficacy end point was sustained virologic response (SVR: HCV RNA <15 IU/mL after 24 weeks without treatment).
  
  
  RESULTS
  Rates of SVR were higher among patients given danoprevir 300 mg (68%), 600 mg (85%), and 900 mg (76%) than placebo (42%) (95% confidence interval: 26%-59%). Seventy-nine percent of patients given danoprevir 600 mg had an eRVR4-20; among these, 96% had an SVR. Serious adverse events were reported in 7% to 8% of patients given danoprevir and 19% given placebo. Four patients given danoprevir (1 patient in the 600-mg group and 3 in the 900-mg group) had reversible, grade 4 increases in alanine aminotransferase, which led to early discontinuation of the 900-mg arm of the study.
  
  
  CONCLUSIONS
  The combination of danoprevir, peginterferon alfa-2a, and ribavirin leads to high rates of SVR in patients with HCV genotype 1 infection, but high doses of danoprevir can lead to grade 4 increases in alanine aminotransferase. Studies of lower doses of danoprevir with ritonavir, to reduce overall danoprevir exposure while maintaining potent antiviral activity, are underway; Clinicaltrials.gov number, NCT00963885.
authors.affiliation: Hôpital Beaujon, Clichy, France. Electronic address: patrick.marcellin@bjn.ap-hop-paris.fr.
authors.forename: Patrick
authors.initials: P
authors.lastname: Marcellin
authors.forename: Curtis
authors.initials: C
authors.lastname: Cooper
authors.forename: Luis
authors.initials: L
authors.lastname: Balart
authors.forename: Dominique
authors.initials: D
authors.lastname: Larrey
authors.forename: Terry
authors.initials: T
authors.lastname: Box
authors.forename: Eric
authors.initials: E
authors.lastname: Yoshida
authors.forename: Eric
authors.initials: E
authors.lastname: Lawitz
authors.forename: Peter
authors.initials: P
authors.lastname: Buggisch
authors.forename: Peter
authors.initials: P
authors.lastname: Ferenci
authors.forename: Martin
authors.initials: M
authors.lastname: Weltman
authors.forename: Emily
authors.initials: E
authors.lastname: Labriola-Tompkins
authors.forename: Sophie
authors.initials: S
authors.lastname: Le Pogam
authors.forename: Isabel
authors.initials: I
authors.lastname: Nájera
authors.forename: Denise
authors.initials: D
authors.lastname: Thomas
authors.forename: Gregory
authors.initials: G
authors.lastname: Hooper
authors.forename: Nancy S
authors.initials: NS
authors.lastname: Shulman
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Mercidita T
authors.initials: MT
authors.lastname: Navarro
authors.forename: Chin Yin
authors.initials: CY
authors.lastname: Lim
authors.forename: Michael
authors.initials: M
authors.lastname: Brunda
authors.forename: Norah A
authors.initials: NA
authors.lastname: Terrault
authors.forename: Ellen S
authors.initials: ES
authors.lastname: Yetzer
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage*; D003521:Cyclopropanes; D004359:Drug Therapy, Combination; D004852:Epoxy Compounds; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000145:classification* / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage*; D054833:Isoindoles; D007769:Lactams / Q000008:administration & dosage*; D047029:Lactams, Macrocyclic; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D011392:Proline / Q000031:analogs & derivatives; D011725:Pyridines; D011994:Recombinant Proteins / Q000008:administration & dosage; D012254:Ribavirin / Q000008:administration & dosage*; D013449:Sulfonamides / Q000008:administration & dosage*
chemical_list: D000998:Antiviral Agents; C402823:CLIK 148; D003521:Cyclopropanes; D004852:Epoxy Compounds; D016898:Interferon-alpha; D054833:Isoindoles; D007769:Lactams; D047029:Lactams, Macrocyclic; D011725:Pyridines; D011994:Recombinant Proteins; D013449:Sulfonamides; D011092:Polyethylene Glycols; D012254:Ribavirin; C553752:danoprevir; D011392:Proline; C100416:peginterferon alfa-2a
keywords: ALT; BMI; CI; Danoprevir (RG7227); HCV; Hepatitis C Virus; PI; Response-Guided Therapy; SVR; Sustained Virologic Response; alanine aminotransferase; body mass index; confidence interval; eRVR; extended rapid virologic response; hepatitis C virus; protease inhibitor; sustained virologic response